News from the FDA-FDA 510(k) Sterility Review Guidance

Thomas J. Callahan

INTRODUCTORY REMARKS

On February 12, 1990, the Center for Devices and Radio- logical Health (CDRH) of the Food and Drug Administra- tion (FDA) implemented the following guidance for sterile devices in the premarket notification (510(k)) process. Sec- tion 510(k) of the Medical Device Amendments of 1976 (May 28, 1976) requires a person who intends to begin in- troduction of a medical device into interstate commerce to notify the FDA at least 90 days in advance.

The Center for Devices and Radiological Health (CDRH) has recently issued a 510(k) Sterility Review Guidance docu- ment to create a more consistent 510(k) review of sterile de- vices among the CRDH review staff. The document can also alert manufacturers to the elements required in sterility as- sessment in 510(k) submissions.

Some of the terminology used in the policy document may need clarification for the non-CDRH reader. The term traditional used in sterilization by traditional methods is not meant to be all inclusive of sterilization methods available at a certain point in time, but rather to designate a group of the most common methods seen by the 510(k) review staff. For these “traditional” methods, a 5 10(k) submission does not need validation data included. Grouping of commonly seen methods which can be characterized by concepts, such as sterility acceptance levels and maximum residue limits, should simplify and expedite reviews.

A separate procedure is described for a group of sterile devices labeled as sterile by a traditional method of steril- ization, but which is also an implant or comes into direct contact with the blood or spinal fluid. The review of this group of devices will now involve the Office of Compliance Surveillance (OCS) and, one Office of Device Evaluation (ODE) division in a Pilot Program to test implementation of a new review procedure. The frequency and degree of OCS involvement and refinement of terms such as inspection “when necessary” and delay of a determination letter “in ex- ceptional cases” will be evaluated and given clearer mean- ing, assuming the ODE/OSC Pilot Program is successful. Manufacturer cooperation and understanding is asked during this trial phase. The thrust of the entire 510(k) Sterility Re- view Guidance document is to reduce the impact of the ste- rility issues in routine 5 1O(k) equivalency determination and in the “exceptional cases” to have the role of OCS doc- umented in a standardized procedure.

REVIEW GUIDANCE

The 510(k) Sterility Review Guidance has been agreed upon by the ODE and the OCS, and endorsed by the Center Di-

Journal of Applied Biomaterials, Vol. 1 , 187-189 (1990) 0 1990 John Wiley & Sons, Inc. CCC 1045-4861/90/020187-03$04‘.00

rector. One purpose of this Guidance is to help assure that the most critical sterile devices reviewed under 510(k)s are manufactured according to Good Manufacturing Practice (GMP) requirements. This will be done by having OCS determine whether an inspection is needed prior to the time an inspection would normally be scheduled. At the same time, it should streamline the review of 510(k)s for sterile devices by concentrating ODE review time on equivalency factors related to design and safety and effectiveness while utilizing the OCS and field expertise on sterile manufac- turing procedures.

EFFECTIVE DATE

Part B of the following review guidance will be effective immediately for all ODE divisions. Part C also will be ef- fective immediately for the division of Cardiovascular De- vices under the Pilot Program. Full implementation of Part C for all other divisions will take place after the conclusion of the Pilot Program. An update of this memorandum will be issued at that time.

* * * * * * * * * * * * *

510(k) STERILITY REVIEW GUIDANCE

A. Purpose

The purpose of this policy is to set forth the respective roles of the Office of Compliance and Surveillance (OCS) and the Office of Device Evaluation (ODE) in regard to the review of premarket notifications (510(k)s) for certain sterile devices.

B. ODE Review Procedures

1 Sterilization by Traditional Methods. The following procedure applies to all 510(k)s for devices labeled as sterile and that have been sterilized by traditional methods of steril- ization, that is, steam, ETO, filtration, or radiation. Devices sterilized by other means are discussed in subsection 2, below. The following information concerning the specifica- tions related to sterility should be collected and reviewed by ODE during the review of the 510(k) for a sterile device:

* The sterilization method that will be used; * A description of the method that will be used to validate

the sterilization cycle, but not the validation data itself; * The sterility assurance level (SAL) for the device which

the firm intends to meet; - A description of the packaging to maintain the device’s sterility (this is not to include packaging integrity testing data);

188 CALLAHAN

* If sterilization involves ETO, the maximum levels of residues of ethylene oxide, ethylene chlorohydrin, and ethylene glycol which remain on the device; - Whether the product is “pyrogen free” and a description of the method used to make that determination;

* The radiation dose, if radiation sterilization will be used.

Only this information will be collected regardless of how the device is labeled, that is, whether it is labeled sterile, sterile until opened or damaged, or sterile until a stated ex- piration date.

We recognize that certain sterilization processes may have a deleterious effect upon a nonsterility aspect of the device. These effects have to be factored into the equivalency deci- sion. Additional guidance on some of these issues will be developed in the future.

For purposes of this guidance document, traditional “steril- ization by radiation” is that which is conducted in accordance with Process Control Guidelines for Gamma Radiation Ster- ilization of Medical Devices as approved by the Association for the Advancement of Medical Instrumentation on March 5 , 1984. An SAL that is or better, is deemed acceptable. If the SAL is higher than this limit, for example, or greater, and this SAL does not seem adequate for the de- vice, the submitter of the 510(k) must identify a predicate device with the same SAL in order for the device to be found equivalent. If the submitter of the 510(k) finds a predicate device with the same SAL, the matter will be referred to OCS to determine whether the products are violative. Other- wise the submitter must adopt a more satisfactory SAL.

This same approach will be applied to residue levels and pyrogens. Concerning ETO residues specifically, levels re- sulting from ETO sterilization that do not exceed the maxi- mum residue limits proposed for Part 821 of Title 21 in the Federal Register of June 23, 1978, or as finalized or amended, will be considered acceptable.

2. Sterilization by New Methods

In addition to the information required in subsection 1, above, for devices sterilized by traditional methods, ODE also will collect and review, for devices sterilized by new methods, the sterilization validation data necessary to deter- mine whether the device is substantially equivalent.

3. Reference Documents. In reviewing 5 10(k)s for ster- ile devices under this guidance, the following references, among others, may be used by ODE reviewers:

* Process Control Guidelines for Gamma Radiation Steril- ization of Medical Devices, AAMI, March 5 , 1984;

* Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices, AAMI, March 31, 1988;

* Guideline on Validation of the Limulus Amebocyte Ly- sate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices, FDA, December, 1987;

* Maximum residue limits for ethylene oxide, ethylene chlorohydnn, and ethylene glycol, Proposed Rule, FDA, 43 Federal Register 27482 (June 23, 1978); and,

* Guideline for Industrial Moist Heat Sterilization of Medi- cal Products, AAMI, August, 1986.

C. ODE/OCS Pilot Program

The pilot program will involve the OCS, the ODE 5 10(k) staff, and the Division of Cardiovascular Devices. This will enable both ODE and the OCS to determine the feasibility, practicality, and resource levels needed to implement this aspect of the guidance. During or after the pilot study, fur- ther modification of the policy may be needed.

1 . ODE will provide the information specified in subsec- tion 2, below, for a device labeled as sterile that has been or will be sterilized by a traditional method as explained in Section B. I . , above, and is the subject of a 510(k) that:

* is also an implant; or, * comes into direct contact with the blood or spinal

Other sterile devices may also be referred to OC on an “as needed” basis.

fluid.

2. Within 15 days of receipt of a 510(k) for a device de- scribed above, ODE will provide to OCS a copy of the route slip for the 510(k) which will contain the follow- ing information, if available in the 510(k):

* The 510(k) number; - The name and address of the manufacturer; * The name of the contact person; * The name of the device; * The proposed use; * The proposed SAL; * The proposed sterilization method; and, - Whether the 5 10(k) contains information support- ing the sterilization method described. This will be rare since validation data, etc., will not be re- quested for traditional methods of sterilization.

3. OCS will review the following data bases for infonna- tion pertaining to the manufacturer’s ability to ade- quately manufacture the sterile device:

- MDR Data Base - Recall Data Base - Government-wide Quality Assurance Data Base * PODS Inspection Data Base * GMP Compliance Program (FD-483) Data Base * Sterility Compliance Program Data Base

4. Based on its findings, and to help assure that the most critical sterile devices reviewed under 5 10(k)s are

NEWS FROM THE FDA 189

manufactured according to GMP requirements, OCS may also:

- Request additional information from the manufac- turer;

a determination letter for up to 90 days from the date of receipt of the 510(k) so that results of an inspection can be reviewed and, if necessary, cor- rection obtained.

. When necessary, immediately issue an assignment for an inspection (this does not mean that inspections are required for 510(k)s, and, when conducted, may be done before or after a finding of substantial equivalence); and, In exceptional cases and within 15 days of its re- ceipt of the routing slip, request that ODE not issue

Both the ODE and OCS staffs will cooperate to the extent necessary to carry out this policy in an efficient and effec- tive manner.

Ann B. Holt Robert L. Sheridan